The present invention relates to novel and therapeutic oxazolidine derivatives of 3-hydroxy-.alpha.-[(methylamino)methyl]-benzyl alcohol, commonly known as phenylephrine, and to pharmaceutical compositions containing the same.
Phenylephrine is a well-known pharmaceutically active amine whose principal use in the field of ophthalmology is as a mydriatic. There are, however, certain known disadvantages associated with the use of phenylephrine as a mydriatic agent. Those disadvantages have limited the use of this highly effective drug. Thus, in spite of the fact that it is one of the most effective mydriatics available, its use is significantly limited because of the significant side effects which may occur in some individuals treated with phenylephrine. Those unwanted significant side effects range from hypertension, syncope, and even in some cases to myocardial infarction, leading to death. Such side effects have been reported with doses of topical ocular phenylephrine.
One approach which has been used from time to time in the past is the effort to develop successful prodrugs of phenylephrine. As those skilled in the art know, the term prodrug refers to a therapeutic agent that requires enzymatic transformation to demonstrate therapeutic activity. In other words, the prodrug itself is not therapeutically active, but once subjected to enzymatic activity by the host organizism it is converted to an active drug. In the past there have been some attempts to make prodrugs of phenylephrine, with varying degrees of success. For example, Mindel et al, "Is Phenylephrine Pivalate a Prodrug?", Arch. Ophthalmol. 98, 2220 (1980) suggests the reaction product of phenylephrine and pivalic acid to provide a pivalic acid ester as a possible prodrug. However, as reported in that article, phenylephrine pivalate itself produces these side effects. And, it goes without saying that to have a successful prodrug, the prodrug itself must not produce the unwanted side effects, even though it may be effectively converted within the body to the active drug. Johansen et al, "Prodrugs as Drug Delivery Systems XXV: Hydrolysis of Oxazolidines--A Potential New Prodrug Type," Journal Pharm. Sci., 72, 1294 (1983) discloses some prodrug possibilities of ephederine. However, ephederine is not commonly used ophthalmically and is biologically different in activity than phenylephrine, with ephederine being used orally for nacolepsy, bronchial asthma and nasal congestion. In contrast, the oxazolidine derivative of phenylephrine increases the bluk considerably on the amine function, the latter of which is responsible for phenylephrine's activity. With the addition of oxazolidine to the amine function, the prodrug would be expected to be devoid of alphaadrenergic activity (A. Burger, "Medicinal Chemistry, 3rd Ed., Wiley-Interscience, 1970, p. 1248).
Accordingly, there is a continuing and real need for safe and effective prodrugs of phenylephrine.
This invention has as its primary objective the development of novel and useful oxazolidine derivatives of phenylephrine, which when used at mydriatically effective levels does not produce side effects similar to phenylephrine, and at the same time is more quickly absorbed across the cornea than phenylephrine.
Another objective of the present invention is to provide a safe and pharmaceutically effective mydriatic which is a prodrug of phenylephrine, prepared from reacting phenylephrine with pivadehyde.
Yet another objective of the present invention is to prepare mydriatic compositions for topical occular treatment, useful in ophthalmic diagnosis and surgery.
Another objective of the present invention is to provide the compounds in a suitable non-aqueous vehicle that possesses increased stability and that can be administered in pharmaceutical formulations to produce a local or systemic physiological effect.
A further objective of the present invention is to provide a method of preparing a prodrug of phenylephrine which comprises reacting phenylephrine with pivaldehyde to produce a product which is stable in oil suspensions but which reverts to phenylephrine upon hydrolysis upon contact with tears.
The method and manner of accomplishing these and other objectives of the invention will become apparent from the detailed description which will follow hereinafter.